Bronx Comprehensive Sickle Cell Center

布朗克斯综合镰状细胞中心

• 批准号: 7261992
• 负责人: Ronald L Nagel
• 金额: $ 9.77万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7261992
• 关键词: clinical research; cooperative study; sickle cell anemia

DESCRIPTION (provided by applicant): This proposal includes: one clinical Project (Project 2: PI: Dr. Fabry) that builds on the pioneering work of the PI in the last cycle on the development of BOLD-MRI and now near infrared spectroscopy (NIRS) to measure oxygenation perfusion and blood volume in sickle cell patients and novel sickle transgenic mice. The objective is to determine if these state-of-the-art technologies can help in the evaluation of sickle damage to brain, kidney and muscle. In addition, there are three Translational Research projects that aim at finding potentially helpful therapeutic interventions in SCD by the pre-clinical development of several basic research strategies. They are: Project 1 (PI: Dr. Acharya) who is interested in generating a globin chain that has more polymerization inhibitory potential than the paradigmatic HbF, based on the pioneering finding, in the previous cycle, that pig-alpha-chain completely neutralizes human beta5-polymerization. The follow-up is to define the minimum number of pig-alpha-chain sequences that are sufficient to confer the desired properties on the human alpha-globin chain. In the process, we will learn about the quinary structure of sickle polymer as well as the refinement of semisynthesis. Project 3 (PI: Dr. Kaul). also builds on work done in the previous cycle, but the present proposal aims at a quantum leap of knowledge as it pertains to: testing the hypotheses that a heterogenous array of red cell integrins and vWF, P-selectin, laminin, and NO are involved in sickle adhesion, and testing the hypothesis that alphaVBeta3 anionic polysaccharides, and hydroxyurea, can be useful in blocking sickle cell adhesion. Project 4 (PI; Dr. Nagel), builds on a long interest in the multigene involvement in the sickle phenotype. This project aims at defining, by state-of-the art microarray technology, the genes responsible for the pleiotropic effects in sickle cell anemia, as well as which of these have epistatic (modifier) capability to define severity risk and to explore potential epigenetic effects in Beta-gene cluster haplotypes linked to the sickle gene. The projects are supported by an Administrative Core, Transgenic Core (in the forefront of developing sickle animal models), by a micro-CHIP Core (supposed also by our in-house Microarray Facility), a strong Clinical and Patient Services Core, that has pioneered the Day Hospital concept into reality, with the purpose of treating sickle cell anemia patients with uncomplicated painful crises in a way that greatly improves their rate of recovery, their hospitalization rates, and that also favorably affects the in house hospitalization length of stay. This proposal is complemented by two above-the-cap Clinical Project Proposals, both based on last cycle accomplishments.

描述（由申请人提供）： 该提案包括：一个临床项目（项目2：PI：Dr. Fabry）建立在PI在上一个周期开发BOLD-MRI和现在的近红外光谱（NIRS）的开创性工作基础上，用于测量镰状细胞患者和新型镰状转基因小鼠的氧合灌注和血容量。 目的是确定这些最先进的技术是否有助于评估镰状对大脑、肾脏和肌肉的损伤。 此外，还有三个转化研究项目，旨在通过几种基础研究策略的临床前开发，找到SCD中潜在有用的治疗干预措施。 它们是：项目1（PI：Acharya博士），他对产生比典型HbF具有更多聚合抑制潜力的球蛋白链感兴趣，基于在前一周期中的开创性发现，即猪α链完全中和人β 5聚合。 后续工作是确定足以赋予人α-珠蛋白链所需性质的猪α-链序列的最小数量。 在这个过程中，我们将了解镰刀形聚合物的五元结构以及半合成的改进。 项目3（主要研究者：Kaul博士）。也建立在前一个周期所做的工作的基础上，但本建议的目的是知识的飞跃，因为它涉及：测试红细胞整联蛋白和vWF，P-选择素，层粘连蛋白和NO的异质阵列参与镰状细胞粘附的假设，并测试α V β 3阴离子多糖和羟基脲可用于阻断镰状细胞粘附的假设。项目4（PI;内格尔博士）建立在对镰状表型中多基因参与的长期兴趣之上。 该项目旨在通过最先进的微阵列技术来定义镰状细胞贫血中负责多效性效应的基因，以及其中哪些基因具有上位性（修饰）能力来定义严重性风险并探索与镰状基因相关的β基因簇单倍型中的潜在表观遗传效应。 这些项目得到了行政核心，转基因核心，（在开发镰刀动物模型的最前沿），通过微芯片核心（也被我们内部的微阵列设施假设），一个强大的临床和患者服务核心，开创了日间医院的概念成为现实，其目的是治疗具有简单的疼痛危象的镰状细胞性贫血患者，从而大大提高他们的康复率，住院率，并且这也有利地影响了住院时间的长短。 该提案由两个上限以上的临床项目提案补充，两者都基于上一周期的成就。